Retinal degeneration is one of the leading causes of visual loss in the world. The mechanism of retinal cell death in different forms of retinal degenerations is not fully understood. There is evidence that a subset of patients with retinopathy may have an autoimmune component to the disease. One possibility is that autoantibodies associated with retinal dysfunction and retinal degeneration could cause retinal damage. Based on clinical and in vitro observations, we propose the hypothesis that autoantibodies may participate in the development of some forms of retinopathies in patients with retinal dysfunction. Some types of human acquired retinopathy may be caused by the action of autoantibodies, functioning through the activation of cell apoptotic responses after prolonged exposure to autoantibodies specific to retinal proteins. When antibodies gain access to the retina through the blood-retinal barrier and penetrate retinal cells, they initiate photoreceptor death by apoptosis. A massive death of retinal cells may lead to significant tissue damage, to visual loss, and finally, to blindness. Antibody penetration into living retinal cells will then constitute a new mechanism of immunologically mediated retinal degeneration. Because the lack of availability of tissue for a direct demonstration of apoptotic cell death in affected retinas of patients, studies using an in vitro model and animal models provide better understanding of the mechanism of cell death induced by immunoglobulins. We propose to use cultured retinal cells and an animal model to study the involvement of autoantibodies in retinal damage. Our long-term goal is to define the mechanism of induction and retinal damage in those autoimmune retinopathies and develop a new in vitro model to analyze the effect of antibody action on retinas. To achieve our goals we propose the following specific aims: (1) Determine whether autoantibodies associated with retinal dysfunction and degeneration are cytotoxic for retinal cells by investigating the relationship between specificity, antibody cell penetration, and cytotoxicity; (2) Define the role of anti-retinal autoantibodies in retinal damage by examining the mechanism of cell entry and the effect of autoantibodies on cell function; (3) Examine the mechanism of cell death in antibody-induced retinal damage by defining the mechanism of antibody-induced apoptosis in retinal cells leading to retinal damage and studying the sensitivity of different retinal cells to antibody-induced apoptosis.